Dementia has been widely recognized as a very serious health problem. Alzheimer's Disease, which has been identified by the National Institutes of Aging as accounting for more than 50% of dementia in the elderly, is the fourth or fifth leading cause of death in Americans over 65 years of age. Four million Americans, 40% of Americans over age 85 (the fastest growing segment of the U.S. population), have Alzheimer's Disease. Twenty-five percent of all patients with Parkinson's Disease also suffer from Alzheimer's Disease. And in about 15% of cases of dementia, Alzheimer's Disease and multi-infact dementia coexist.
The precise molecular lesion(s) of the brain responsible for the morphological and functional deficits associated with Alzheimer's Disease is unclear despite intensive research efforts over the last decade. However, the most consistent abnormality found in Alzheimer's Disease, as well as in vascular dementia and cognitive impairments due to organic brain disease related directly to alcoholism (the second and third most common causes of dementia), is the degeneration of the cholinergic neurotransmitter system arising from the basal forebrain to both the cortex and hippocampus (Bigl et al., In: Brain Cholinergic Systems, eds. M. Steriade and D. Biesold, Oxford University Press, Oxford, 1990, pp. 364-386). Neurochemical evidence from the brains of patients afflicted with Alzheimer's Disease has revealed consistent decreases in markers of cholinergic neuronal function (Perry et al., Br. Med. J. 1978, 2:1457; Reisine et al., Brain Res. 1978, 159:477; Coyle et al., Science 1983, 219:1184; McGeer et al., Neurology 1984, 34:741). Although a number of other neurotransmitter systems are affected in Alzheimer's Disease (Davies, Med. Res. Rev. 1983, 3:221), the relative occurrence of such abnormalities is less consistent or the affect is less profound.
Degeneration of the cholinergic neurotransmitter system is not limited to individuals suffering from dementia, however, but has also been seen in uninflicted aged adults and rats. Decreases in cholinergic markers in the basal forebrain, decreases in cortical activities of the biosynthetic and degradative enzymes for acetylcholine, decreases in the ability to release acetylcholine from brain tissue slices, and decreases in numbers of cholinergic receptors have all been reported (for review, see Giacobini, J. Neurosci. Res. 1990, 27:548). Moreover, for those cholinergic neurons that remain, aging may cause a decrease in the temporal fidelity of existing impulse flow from the basal forebrain to the cortex (Aston-Jones et al., Brain Res. 1985, 325:271). Consistent with these findings are pharmacological studies suggesting that impairment of cholinergic mechanisms are, at least in part, responsible for the memory disturbances in aged humans and animals (Drachman and Leavitt, Arch. Neurol. 1974, 30:113; Bartus et al., Science 1982, 217:408).
Other clinical correlates associated with the neurodegenerative process of Alzheimer's Disease include decreases in cerebral blood flow and cerebral glucose utilization, which occur largely in parallel with cholinergic deficits (Ingvar and Risberg, Exp. Brain Res., 1962, 3:195; Ingvar et al., Vol. 7 Aging: Alzheimer's Disease. Senile Dementia and Related Disorders, eds. R. Katzman, R. D. Terry, and K. L. Bick, Raven Press, 1978, p. 203; Dastur, J. Cerebral Blood Flow & Metabol. 1985, 5:1). In fact, it has been suggested that routine measurement of cerebral blood flow may be a useful procedure in evaluating patients suspected of having dementia, and of Alzhemimer's Disease in particular.
Conflicting opinions have been expressed in the literature about the effect of aging on resting cerebral blood flow and cerebral glucose utilization in "normal healthy" humans (Dastur, J. Cerebral Blood Flow & Metabol. 1985, 5:1,) and rats (Smith et al., Brain 1980, 103:351; Buchweitz-Milton and Weiss, Neurobiol. Aging 1987, 8:55), but it has been recently reported that increases in cerebral blood flow elicited by electrical stimulation of the basal forebrain in rats result in age-related impairments (Linville and Arneric, Soc. Neurosci. Abstract 1989, 15:17.5). Also, studies that compare the degree of learning impairment with the degree of reduced cortical cerebral blood flow in aged rats show a good correlation (Berman et al., Neurobiol. Aging 1988, 9:691).
Chronic alcoholism, like Alzheimer's Disease and normal aging, is also characterized by diffuse reductions in cerebral blood flow in those brain regions where cholinergic neurons arise (basal forebrain) and project to (cerebral cortex) (Lofti & Meyer, Cerebrovasc. and Brain Metab. Rev. 1989, 1:2). Moreover, of all the neurotransmitter systems studied, the neurotoxic effects of alcohol on the cholinergic system are thought to be the most important.
Intuitively, regardless of specific etiologic process, therapies directed towards enhancing cognitive processing would be contingent upon maintaining a well regulated balance between adequate cerebral blood flow, cerebral glucose utilization and cholinergic neurotransmission arising from the basal forebrain.
Recent clinical evidence suggests that the characteristic perfusion abnormality observed in Alzheimer's Disease patients reflects regional nicotinic cholinergic deficits (Prohovnik, Neurobiol. Aging 1990, 11:262). In particular, mecamylamine, a centrally acting nicotinic receptor antagonist, was found to reduce resting cortical perfusion in the parietotemporal cortex of humans, the area of the cortex most consistently found to be impaired in functional brain imaging of Alzheimer's Disease patients. In agreement with this finding, regulation of cerebral blood flow in the frontoparietal cortex, governed by the basal forebrain, is also dependent upon nicotinic mechanisms in the rat (Arneric, J. Cerebral Blood Flow & Metabol. 1989, 9 (Suppl. 1): S502).
Pilot clinical studies suggest that nicotine may be useful for the acute treatment of deficits in attention and information processing associated with Alzheimer's Disease (Sahakian et al., Brit. J. Psych. 1989, 154:797; Newhouse et al., Psychopharmacol. 1988, 95:171). Anecdotal evidence has suggested a negative correlation between Alzheimer's Disease and smoking, and both acutely and chronically administered nicotine were found to enhance cognitive function in rats (Levin et al., Behav. Neural Biol. 1990, 53:269), an effect that is preserved in aged animals (Cregan et al., 1989, 15:295.2). These clinical findings are supported by animal studies demonstrating a regenerative/protective action of chronically administered nicotine on both neuronal and vascular functions following destruction of the nigro-striatal dopamine system (Janson et al., Prog. Brain Res. 1989, 79:257; Owman et al., Prog. Brain Res. 1989, 79:267). Interestingly, in contrast to the classical down-regulation of receptors typically seen with receptor agonists, chronic nicotine administration up-regulates (50-100%) the number of acetylcholine receptors without affecting the affinity of acetylcholine for the receptor (Benwell et al., J. Neurochem. 1988, 50:1243). This effect occurs both in humans and smaller animals such as rats (Lapchack et al., J. Neurochem. 1989, 52:483).
Substantial reductions (30-50%) in nicotinic receptors have been consistently reported in the brains of patients with Alzheimer's Disease and Parkinson's Disease (Kellar et al., Brain Res., 1987, 436:62; Whitehouse et al., Neurol. 1988, 38:720). Modest age-related reductions in cortical nicotinic receptors are also seen in otherwise healthy individuals. In addition, with chronic drug administration nicotine may work to restore receptor numbers and foster neuronal plasticity.
On the other hand, changes in muscarinic receptors are less remarkable and more dependent on receptor subtype. In fact, it has been reported that postsynaptic muscarinic acetylcholine receptors are generally preserved in Alzheimer's patients and that agonists capable of stimulating these receptors directly would be useful in correcting the cholinergic deficiency in Alzheimer's Disease and in the treatment of the memory impairment symptom of cerebral insufficiency (F.V. DeFeudis, Drugs of Today, 1988, 24, 473-490).
Existing cholinergic agonists, however, are therapeutically sub-optimal. This is due to unfavorable pharmacokinetics (e.g., arecoline and nicotine), poor potency and lack of selectivity (e.g., RS-86, a centrally active agonist developed by Sandoz), poor CNS penetration (e.g., carbachol) or poor oral bioavailability (e.g., nicotine). RS-86, for example, has similar affinity for cholinergic receptors located in the heart and cortical tissues and is a full agonist at cardiac receptors, whereas it is only a partial agonist at cortical receptors (S. B. Freedman, British Journal of Pharmacology, 1986, 87:29P). In addition, known compounds have many unwanted central agonist actions, including hypothermia, hypolocomotion and tremor. Peripheral side effects include miosis, lacrimation defecation and tachycardia (Benowitz et al., In: Nicotine Psychopharmacology eds. S. Wonnacott, M. A. H. Russell, & I. P. Stolerman, Oxford University Press, Oxford, 1990, pp. 112-157; M. Davidson, et al, In Current Research in Alzheimer Therapy; E. Giacobini and R. Becker, Ed.; Taylor & Francis: New York, 1988; pp 333-336).
Alternatively, the enhancement, via a positive allosteric modulation, of the efficacy with which the andogenous ligand, acetylcholine, binds to the nicotinic and/or the muscarinic cholinergic receptor offers significant potential for the treatment of cognitive dysfunction. Sloan and co-workers (Life Sci. 1985, 37:1367) suggest that the (+)isomer of (.+-.)2-methylpiperidine enhances the binding of nicotinic ligand to rat brain receptor sites. This type of interaction can be functionally expressed by enhanced nicotinic cholinergic transmission. The advantage of such an approach is that only ongoing cholinergic neurotransmission would be enhanced, and the potential for side-effects, such as, for example, cardiovascular side effects, and dependence liabilities would be greatly diminished.
Spirocyclic compounds have been disclosed for a variety of utilities. For example, J. P. P. Heykants in Life Sciences 1969, 8:1029-1039, discloses 1-phenyl-1,3,8-triazaspiro[4,5]decan-2,4-dione as a major product of the metabolism of the neuroleptic drug, fluspirilene, in the rat. P. L. Feldman and M. F. Brackeen in J. Org. Chem. 1990, 55:4207-4209, report an improved synthesis of the analgesic, carfentanil, via the intermediate, 8-benzyl-1-phenyl-1,3,8-triazaspiro[4,5]decane-2,4-dione, by a modified Strecker synthesis and G. Winters, et al. in Farmaco, Ed Sci. 1970, 25:681-693, disclose the preparation of spirohydantoins, including the 1',3'-diphenylspirohydantoin derivative of N-butyl-4-piperidone, by a modified Strecker synthesis. Also, Ugi, et al. in Liebig's Ann. 1963, 666:54-61 and Ang. Chem, 1962, 74:9-21, described the preparation of spirohydantoin derivatives of cyclohexanone and U.S. Pat. No. 4,162,246, issued Jul. 24, 1979, and assigned to Sankyo Company Limited, is representative of a series of patents and publications authored by Sankyo scientists describing the preparation of oligiomeric spirohydantoin derivatives of 2,2,6,6-tetraalkylpiperidine and their use as polymer stabilizers. However, these references describing the synthesis of spirocyclic hydantoins do not suggest the novel compounds of the present invention which interact with and enhance central cholinergic neurotransmission.
Several other references have shown spirocyclic piperidines which have central nervous system utility, but disclose compounds which are chemically quite different from our novel compounds. French Patent 1,291,532, assigned to Sandoz S. A., discloses substituted spirosuccinimides of the formula ##STR2## wherein R.sup.1 and R.sup.2 are each hydrogen or lower alkyl, including the compound, 3-ethyl-8-methyl-2,8-diazaspiro[4,5]decane-1,3-dione (referred to herein as RS-86), having parasympathicomimetic activity. Bollinger, U.S. Pat. No. 4,735,944, issued Apr. 5, 1988, discloses spiro-dioxolanes, spirodithiolanes and spiro-oxothiolanes for use in mental therapy and Tsukamoto, et al., European Patent Application No. EP0311313, published Apr. 12, 1989, discloses heterocyclic spiro compound which act upon muscarinic acetylcholine receptors.